N-Substituted Valiolamine Derivatives as Potent Inhibitors of Endoplasmic Reticulum α-Glucosidases I and II with Antiviral Activity

J Med Chem. 2021 Dec 23;64(24):18010-18024. doi: 10.1021/acs.jmedchem.1c01377. Epub 2021 Dec 6.

Abstract

Most enveloped viruses rely on the host cell endoplasmic reticulum (ER) quality control (QC) machinery for proper folding of glycoproteins. The key ER α-glucosidases (α-Glu) I and II of the ERQC machinery are attractive targets for developing broad-spectrum antivirals. Iminosugars based on deoxynojirimycin have been extensively studied as ER α-glucosidase inhibitors; however, other glycomimetic compounds are less established. Accordingly, we synthesized a series of N-substituted derivatives of valiolamine, the iminosugar scaffold of type 2 diabetes drug voglibose. To understand the basis for up to 100,000-fold improved inhibitory potency, we determined high-resolution crystal structures of mouse ER α-GluII in complex with valiolamine and 10 derivatives. The structures revealed extensive interactions with all four α-GluII subsites. We further showed that N-substituted valiolamines were active against dengue virus and SARS-CoV-2 in vitro. This study introduces valiolamine-based inhibitors of the ERQC machinery as candidates for developing potential broad-spectrum therapeutics against the existing and emerging viruses.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology*
  • Binding Sites
  • Chlorocebus aethiops
  • Crystallography, X-Ray
  • Dengue Virus / drug effects
  • Endoplasmic Reticulum / enzymology
  • Glycoside Hydrolase Inhibitors / chemical synthesis
  • Glycoside Hydrolase Inhibitors / metabolism
  • Glycoside Hydrolase Inhibitors / pharmacology*
  • Humans
  • Imino Sugars / chemical synthesis
  • Imino Sugars / metabolism
  • Imino Sugars / pharmacology*
  • Inositol / analogs & derivatives*
  • Inositol / chemical synthesis
  • Inositol / metabolism
  • Inositol / pharmacology
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Protein Binding
  • SARS-CoV-2 / drug effects
  • Vero Cells
  • alpha-Glucosidases / chemistry
  • alpha-Glucosidases / metabolism*

Substances

  • Antiviral Agents
  • Glycoside Hydrolase Inhibitors
  • Imino Sugars
  • Inositol
  • valiolamine
  • 4-nitrophenyl-alpha-glucosidase
  • glucosidase I
  • alpha-Glucosidases